Regulation of gene expression at the translational level. Our experimental model system is the translational control of mammalian TOP mRNAs. These mRNAs encode many components of the protein synthesis machinery in higher eukaryotes, are characterized by the presence of a consensus structural motif at their 5’ terminus (5' Terminal OligoPyrimidine tract), and are translationally regulated by mitogenic and nutritional signals. Our studies have focused on the establishment of the pathway that transduces external signals into translation efficiency of TOP mRNAs, and on the identification of the trans-acting factor that directly interacts with them and thus mediates their translational regulation. Elucidation of the mechanism(s) by which ribosomal protein S6 phosphorylation plays its physiological role in determination of tumorigenicity. To directly address this issue we have established viable and fertile mice, whose ribosomal protein S6 is mutated and therefore cannot be phosphorylated. These knockin mice, and cells derived from them, have enabled us to implicate ribosomal protein S6 phosphorylation as a determinant of the size and proliferation of cells. Interestingly, rS6 phosphorylation deficiency can protect mice from the development of cancer in the endocrine and exocrine pancreas, whether induced by oncogenes or carcinogen. We are currently study the mechanism underlying the positive role of rpS6 phosphorylation in neoplastic transformation.